Tuberculosis (TB) is a serious public health issue and rational development of effective vaccines requires that we understand the cellular mechanisms mediating protective immunity; this is the focus of the current proposal. We show here that vaccine-induced memory to Mycobacterium tuberculosis (Mtb) can limit bacterial growth but that under conditions that mimic a natural exposure, the expression of memory Is delayed. Crucially, this delay allows bacterial growth to occur. This growth results in inflammation and the alteration of the environment in which the memory response is expressed. Based on our published and preliminary data we propose the following: Appropriate vaccination induces a population of surveillance cells that populate the lung. These cells respond to infection by initiating IL-17 release and subsequent chemokine induction, which recruits effector IFN-y producing memory cells capable of stopping bacterial growth. To improve vaccination we need to determine how to generate a memory response that can respond rapidly to Mtb infection in the lung and we need to identify a population of cells capable of not only stopping bacterial growth but capable of killing bacteria in the lung. In this new application therefore we want to address two related issues using our working model as a base. The first is the determination of the factors regulating the induction and function of the memory T cell response to TB in the lung (Aim One). The second is the identification of crucial functional attributes of the effector cells capable of mediating immunity to Mtb challenge in the lung (Aim Two). In this new submission we will utilize Mtb-specific TcRTg mice, cytokine- reporter mice and tetramer reagents to analyze antigen-specific responding cells. We will also utilize a proven cell transfer model to investigate the ability of defined subsets of T cell to mediate protection against pulmonary challenge with Mtb. In conjunction with Project 1 we will identify the factors regulating CD4 T cell subsets as well as determining whether novel subsets of cells are active against Mtb. With Project 2 we generate CDS T cell subsets specific for Mtb and determine the ability of these subsets to protect against Mtb. With Project 3 we will determine the ability of selectin-binding activity to identify subsets of cells induced by vaccination and Mtb Infection and determine whether PSGL-1 activity regulates the protective ability of memory T cells. RELEVANCE (See instructions): We know too little about how the vaccine-induced protective response to tuberculosis works. If we do not know how the response works it is difficult to improve upon it. By investigating the way the response works we have identified new cell types that can be targeted by vaccination. We will investigate how these cells are regulated and this will have the potential to improve the protective effect of vaccines and thereby reduce the incidence of tuberculosis in the world. This will have a significant impact in worldwide public health.